Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents, platinum compounds ATC code: L01XA 03

Oxaliplatin is an antineoplastic active substance belonging to a new class of platinum-based compounds in which the platinum atom is complexed with 1, 2-diaminocyclohexane ("DACH") and an oxalate group.
Oxaliplatin is a single enantiomer, (SP-4-2)-[(1R, 2R)-Cyclohexane-1, 2-diamine-kN,kN'] [ethanedioato(2- )- kO1, kO2] platinum.

Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumour activity in a variety of tumour model systems, including human colorectal cancer models.
Oxaliplatin also demonstrates in vitro and in vivo activity in various cisplatin-resistant models.
A synergistic cytotoxic action has been observed in combination with 5-fluorouracil both in vitro and in vivo.
Studies on the mechanism of action, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin interact with DNA to form both intra and inter-strand crosslinks, resulting in the disruption of DNA synthesis leading to cytotoxic and antitumour effects.

In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m2 repeated every two weeks) combined with 5-fluorouracil/folinic acid (5-FU/FA) is reported in three clinical studies: 
- In a front-line treatment, the 2-arm comparative phase III EFC2962 study randomised 420 patients either to 5-FU/FA alone (LV5FU2, N=210) or the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=210); 
- In pretreated patients, the comparative three arms phase III study EFC4584 randomised 821 patients refractory to an irinotecan (CPT-11) + 5-FU/FA combination either to 5-FU/FA alone (LV5FU2, N=275), oxaliplatin single agent (N=275), or combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=271).

- Finally, the uncontrolled phase II EFC2964 study included patients refractory to 5-FU/FA alone, that were treated with the oxaliplatin and 5-FU/FA combination (FOLFOX4, N=57).

The two randomised clinical trials, EFC2962 in front-line therapy and EFC4584 in pretreated patients, demonstrated a significantly higher response rate and a prolonged progression free survival (PFS)/time to progression (TTP) as compared to treatment with 5-FU/FA alone.

In EFC4584 performed in refractory pretreated patients, the difference in median overall survival (OS) between the combination of oxaliplatin and 5-FU/FA did not reach statistical significance.


Response rate under FOLFOX4 versus LV5FU2
Response rate, % (CI 95%)                                                               Oxaliplatin single agent Independent radiological                     LV5FU2                FOLFOX4 review ITT analysis


First-line treatment                           22                        49 EFC2962                                      (16-27)                   (42-56 )                    NA* Response assessment every                            P value = 0.0001 8 weeks
Pretreated patients
EFC4584                                       0.7                       11.1                       1.1 (refractory to CPT-11 + 5-FU/FA)       (0.0 - 2.7)         (7.6 - 15.5)                       (0.2 - 3.2) Response assessment every 6                       P value < 0.0001 weeks
Pretreated patients EFC2964
(refractory to                                 NA*                       23                         NA* 5-FU/FA)                                                               (13-36) Response assessment every
12 weeks

*NA: not applicable

Median Progression Free Survival (PFS) / Median Time to Progression (TTP): FOLFOX4 versus LV5FU2
Median PFS/TTP, months
(CI 95%)                             LV5FU2                 FOLFOX4                  Oxaliplatin single agent Independent radiological review ITT analysis
First-line treatment                  6.0                        8.2
EFC2962 (PFS)                     (5.5 - 6.5)         (7.2 - 8.8)                               NA* Log-rank P value = 0.0003
Pretreated patients
EFC4584 (TTP)                         2.6                        5.3                            2.1 (refractory to CPT-11 + 5-     (1.8 - 2.9)             (4.7 - 6.1)                (1.6 - 2.7) FU/FA )                        Log-rank P value < 0.0001
Pretreated patients
EFC2964 (refractory to                NA*                       5.1                             NA* 5-FU/FA)                                                    (3.1 - 5.7) *NA: not applicable



Median Overall Survival (OS) under FOLFOX4 versus LV5FU2

Median OS, months                       LV5FU2                     FOLFOX4                   Oxaliplatin (95% CI)                                                                                    Single agent ITT analysis


Front-line treatment                      14.7                        16.2                      NA* EFC2962                                (13.0-18.2)                 (14.7-18.2) Log-rank P value = 0.12

Pretreated patients

EFC4584                                    8.8                        9.9 8.1

(refractory to CPT-11 + 5-             (7.3 - 9.3)                 (9.1-10.5) FU/FA)                                                                                        (7.2-8.7) Log-rank P value = 0.09

Pretreated patients
10.8
EFC2964 (refractory to                     NA*                                                  NA* (9.3-12.8)
5FU/FA)

*NA: not applicable

In pretreated patients (EFC4584), who were symptomatic at baseline, a higher proportion of those treated with oxaliplatin and 5-FU/FA experienced a significant improvement of their disease-related symptoms compared to those treated with 5-FU/FA alone (27.7% vs 14.6%, p = 0.0033). In non pretreated patients (EFC2962), no statistically significant difference between the two treatment groups was found for any of the quality of life dimensions. However, the quality of life scores were generally better in the control arm for measurement of global health status and pain and worse in the oxaliplatin arm for nausea and vomiting.

In the adjuvant setting, the MOSAIC comparative phase III study (EFC3313) randomised 2246 patients (899 stage II/Duke's B2 and 1347 stage III/Duke's C) further to complete resection of the primary tumour of colon cancer either to 5-FU/FA alone (LV5FU2, N=1123 ( B2/C = 448/675) or to combination of oxaliplatin and 5FU/FA (FOLFOX4, N=1123 (B2/C) = 451/672).

EFC3313: Disease-free survival at 3 years (ITT analysis)* in the overall population Treatment arm                                       LV5FU2                              FOLFOX4 Percent disease-free survival at 3 years (95% CI)                73.3                                                78.7 (70.6 - 75.9)                                       (76.2 - 81.1)
Hazard ratio (95% CI)                                                    0.76 (0.64 - 0.89)

Stratified log rank test                                               P =0.0008 * Median follow-up at 44.2 months (all patients followed for at least 3 years).


The study demonstrated an overall significant advantage in 3-year disease free survival for the oxaliplatin and 5-FU/FA combination (FOLFOX4) over 5-FU/FA alone (LV5FU2).



EFC3313: Disease-free survival at 3 years (ITT analysis)* according to stage of disease 
Patient stage                  Stage II (Duke‘s B2)                     Stage III (Duke‘s C) 
Treatment arm                      LV5FU2             FOLFOX4              LV5FU2              FOLFOX4 Percentage disease free survival at 3 years                  84.3                   87.4             65.8                    72.8 (95% CI)                         (80.9 - 87.7)       (84.3 - 90.5)       (62.2 - 69.5)        (69.4 - 76.2) Hazard ratio (95% CI)                           0.79                                     0.75 (0.57 - 1.09)                            (0.62 - 0.90)
Log rank test                                P = 0.151                                P = 0.002 
* Median follow-up at 44.2 months (all patients followed for at least 3 years).

Overall Survival (ITT analysis):
At time of the analysis of the 3-year disease free survival, which was the primary endpoint of the MOSAIC trial, 85.1% of the patients were still alive in the FOLFOX4 arm versus 83.8% in the LV5FU2 arm. This translated into an overall reduction in mortality risk of 10% in favour of FOLFOX4 not reaching statistical significance (hazard ratio = 0.90). The figures were 92.2% versus 92.4% in the stage II (Duke's B2) subpopulation (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III (Duke's C) sub-population (hazard ratio = 0.87), for FOLFOX4 and LV5FU2, respectively.



Oxaliplatin single agent has been evaluated in paediatric population in 2 Phase I (69 patients) and 2 Phase II (166 patients) studies. A total of 235 paediatric patients (7 months-22 years of age) with solid tumors have been treated. The effectiveness of oxaliplatin single agent in the paediatric populations treated has not been established. Accrual in both Phase II studies was stopped for lack of tumor response.

Treatment regimen with FOLFIRINOX (oxaliplatin, leucovorin, irinotecan and 5-fluorouracil) 
In patients with metastatic pancreatic adenocarcinoma not previously treated with chemotherapy, oxaliplatin was evaluated in PRODIGE 4/ACCORD 11 study (N = 342). The intent-to-treat population included 171 patients groups and the safety population (all patients who received treatment) included 167 patients in the FOLFIRINOX group and 169 patients in the Gemcitabine group.
Patients were randomized in a 1:1 ratio with stratification by site, performance status (0 vs. 1) and primary tumor location (head vs. body or tail of the pancreas), to receive FOLFIRINOX (oxaliplatin 85 mg/m 2, leucovorin 400 mg/m 2 irinotecan 180 mg/m 2, 5-fluorouracil 400 mg/m 2 IV bolus followed by 2,400 mg/m2 continuous IV infusion for 46 hours every 14 days) or gemcitabine (1000 mg/m 2 IV over 30 minutes, weekly for 7 weeks followed by 1-week rest, then weekly for 3 weeks in subsequent 4-week cycles). Each cycle was defined as being a period of 2 weeks for both regimens. Six months of chemotherapy were recommended for patients who had a response.

The median number of treatment cycles administered was 10 (range 1-47) in FOLFIRINOX arm and 6 (range 1-26) in Gemcitabine arm (p <0.001). The median duration of follow-up of patients was 26.6 months (95% CI:  20.5 to 44.9). The median relative dose intensities of fluorouracil, irinotecan, oxaliplatin and gemcitabine were
82%, 81%, 78% and 100%, respectively. More patients in Gemcitabine group had disease progression prior to complete 12 cycles (6 months) of treatment (79.9% vs 54.6% in FOLFIRINOX group, p <0.001).

The median overall survival was significantly higher in FOLFIRINOX arm compared to Gemcitabine arm (11.1 months vs. 6.8 months, HR = 0.57, 95% CI: 0.45 to 0.73, p <0.001). The overall survival rates after 6, 12 and 18 months were higher for all patients treated with FOLFIRINOX (75,9%, 48,4% and 18,6% respectively) compared with 57,6%, 20,6% and 6,0%, respectively for those treated with gemcitabine.

The median progression-free survival was significantly higher in FOLFIRINOX arm compared to Gemcitabine arm (6.4 months vs. 3.3 months, HR = 0.47, 95% CI: 0.37 to 0.59, p <0.001). The objective response rate was 

31.6% in FOLFIRINOX group versus 9.4% in Gemcitabine group (p <0.001). The beneficial effect of FOLFIRINOX was similar in all subgroups of patients.

This data are summarized in the following table.

Summary of Efficacy results of FOLFIRINOX versus Gemcitabine
FOLFIRINOX            Gemcitabine        Hazard         p-Value
(N=171)               (N=171)            Ratio


Complete Response (CR)                  1 (0.6%)              0 (0%)
Partial Response (PR)                   53 (31%)              16 (9.4%) 
Objective Response rate (CR + PR)      54 (31.6%)            16 (9.4%)                         < 0.001 
95%CI                                  24.7–39.1             5.4–14.7 
Stable Disease (SD)                    66 (38.6%)            71 (41.5%) < 0.001
Disease Control (CR + PR + SD)         120 (70.2%)           87 (50.9%) 
95%CI                                  62.7–76.9             43.1–58.6 
Median Overall Survival (months        11.1                  6.8                0.57           < 0.001 
95%CI                                  9.0–13.1              5.5–7.6            0.45–0.73 
1-year Survival                        48.4%                 20.6%

18-month Survival                      18.6%                 6%
Median Progression-free survival       6.4                   3.3                0.47           < 0.001 (months)

95%CI                                  5.5–7.2               2.2–3.6            0.37–0.59 

Safety results

Patients who received FOLFIRINOX had significantly higher rates of grade 3 and 4 neutropenia (45.7% vs.
21%), febrile neutropenia (5.4% vs. 1.2%), thrombocytopenia (9.1% vs. 3 6%), diarrhea (12.7% vs. 1.8%),
and sensory neuropathy (9% vs. 0%). Cholangitis was not observed in either group.

Filgrastim was administered in 42.5% of patients receiving FOLFIRINOX and 5.3% of patients who received gemcitabine.


Quality of life
Despite the high incidence of adverse events associated with FOLFIRINOX regimen, there was a significant increase in time to definitive Quality of Life deterioration in FOLFIRINOX group compared to gemcitabine group.

At 6 months, 31% of patients in the FOLFIRINOX group had a definitive decrease in their scores on the Global Health Status and Quality of Life scale compared to 66% in the Gemcitabine group (HR = 0.47, 95% CI: 0.30 – 0.70, p<0.001). In the FOLFIRINOX group, the time to definitive deterioration in the quality of life was significantly increased in all items of the EORTC QLQ-C30 questionnaire. except the time to a definitive decrease in the scores associated with insomnia, diarrhea, and financial difficulties caused by a physical condition or medical treatment, which did not differ significantly between regimens.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

The pharmacokinetics of individual active compounds have not been determined. The pharmacokinetics of ultrafiltrable platinum, representing a mixture of all unbound, active and inactive platinum species, following a two-hour infusion of oxaliplatin at 130 mg/m 2 every three weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m 2 every two weeks for 1 to 3 cycles are as follows:

Summary of Platinum Pharmacokinetic Parameter Estimates in Ultrafiltrate Following Multiple Doses of oxaliplatin at 85 mg/m2 Every Two Weeks or at 130 mg/m2 Every Three Weeks 

Dose           Cmax        AUC0-48          AUC          t1/2α       t1/2β       t1/2γ        Vss   CL μg/mL       μg.h/mL        μg.h/mL           h         h            h           L    L/h 85 mg/m2
Mean              0.814         4.19           4.68         0.43        16.8        391          440   17.4 SD                0.193         0.647          1.40         0.35        5.74        406          199   6.35 130 mg/m2
Mean               1.21         8.20           11.9         0.28        16.3        273          582   10.1 SD                 0.10         2.40           4.60         0.06        2.90        19.0         261   3.07 2
2
Mean AUC0-48 , and Cmax values were determined on Cycle 3 (85 mg/m ) or Cycle 5 (130 mg/m ). Mean AUC, Vss and CL values were determined on Cycle 1.
Cmax , AUC, AUC0-48 , Vss and CL values were determined by non-compartmental analysis. t1/2α, t1/2β, and t1/2γ, were determined by compartmental analysis (Cycles 1-3 combined).


At the end of a 2-hour infusion, 15% of the administered platinum is present in the systemic circulation, the remaining 85% being rapidly distributed into tissues or eliminated in the urine. Irreversible binding to red blood cells and plasma, results in half-lives in these matrices that are close to the natural turnover of red blood cells and serum albumin. No accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two  weeks or 130 mg/m2 every three weeks and steady state was attained by cycle one in this matrix. Inter- and intra-subject variability is generally low.

Biotransformation in vitro is considered to be the result of non-enzymatic degradation and there is no evidence of cytochrome P450-mediated metabolism of the diaminocyclohexane (DACH) ring. Oxaliplatin undergoes extensive biotransformation in patients, and no intact drug was detectable in plasma ultrafiltrate at the end of a 2-hour-infusion. Several cytotoxic biotransformation products including the monochloro-, dichloro- and diaquo-DACH platinum species have been identified in the systemic circulation together with a number of inactive conjugates at later time points.

Platinum is predominantly excreted in urine, with clearance mainly in the 48 hours following administration.

By day 5, approximately 54% of the total dose was recovered in the urine and < 3% in the faeces.
The effect of renal impairment on the disposition of oxaliplatin was studied in patients with varying degrees of renal function. Oxaliplatin was administered at a dose of 85 mg/m 2 in the control group with a normal renal function (CLcr > 80 ml/min, n=12) and in patients with mild (CLcr = 50 to 80 ml/min, n=13) and moderate (CLcr = 30 to 49 ml/min, n=11) renal impairment, and at a dose of 65mg/m 2 in patients with severe renal impairment (CLcr < 30 ml/min, n=5). Median exposure was 9, 4, 6, and 3 cycles, respectively, and PK data at cycle 1 were obtained in 11, 13, 10, and 4 patients respectively.

There was an increase in plasma ultrafiltrate (PUF) platinum AUC, AUC/dose and a decrease in total and renal CL and Vss with increasing renal impairment especially in the (small) group of patients with severe renal impairment: point estimate (90% CI) of estimated mean ratios by renal status versus normal renal function for AUC/dose were 1.36 (1.08, 1.71), 2.34 (1.82, 3.01) and 4.81 (3.49, 6.64) for patients with mild and moderate and in severe renal failure respectively.


Elimination of oxaliplatin is significantly correlated with the creatinine clearance. Total PUF platinum CL was respectively 0.74 (0.59, 0.92), 0.43 (0.33, 0.55) and 0.21 (0.15, 0.29) and for Vss respectively 0.52 (0.41, 0.65), 0.73 (0.59, 0.91) and 0.27 (0.20, 0.36) for patients with mild, moderate and severe renal failure  respectively. Total body clearance of PUF platinum was therefore reduced by respectively 26% in mild, 57% in moderate, and 79% in severe renal impairment compared to patients with normal function.

Renal clearance of PUF platinum was reduced in patients with impaired renal function by 30% in mild, 65% in moderate, and 84% in severe renal impairment compared to patients with normal function.

There was an increase in beta half life of PUF platinum with increasing degree of renal impairment mainly in the severe group. Despite the small number of patients with severe renal dysfunction, these data are of concern in patients in severe renal failure and should be taken into account when prescribing oxaliplatin in patients with renal impairment (see sections 4.2:”Posology and method and administration, 4.3:”Contraindications” and 4.4:”Special warnings and special precautions for use”).